Nucleotides are some of the most ubiquitous compounds in nature, one example of which is the adenosine triphosphate ("ATP") molecule shown below: ##STR1##
The four principal ribonucleotide triphosphates may be polymerized to provide "RNA," or "ribonucleic acid." In addition to its role in all normal cells, RNA represents the genetic material of one major class of pathogenic viruses known as the RNA viruses, examples of which are HIV and herpes viruses. When the sugar moiety is deoxyribose, the four principal deoxyribonucleotide triphosphates are polymerized into deoxyribonucleic acid strands, or "DNA," the genetic material of all plants and animals. There is also another class of pathogenic viruses known as DNA viruses, examples of which include measles and mumps.
Much of the cell's chemistry with regard to these various nucleotide compounds involves the addition, removal or transfer of one or more of the phosphates groups within the triphosphate moiety, as illustrated by the equilibrium transphosphorylation reaction wherein a phosphate group is transferred between uridine diphosphate ("UDP") and ATP to give uridine triphosphate ("UIp") and adenosine diphosphate ("ADP"): ##STR2##
The body triphosphorylates and dephosphorylates drug and metabolic intermediates at extremely high rates, resulting in a constant low level of triphosphorylated materials that are then used in cellular processes. Phosphates, pyrophosphates and triphosphates of antiviral drugs, nucleosides, inositol, isoprenoids, and other biochemical building blocks are critical intermediates in the biosynthesis of nucleosides, proteins and hormones.
In spite of the presence of phosphorylated compounds throughout the body, such compounds are elusive as pharmacological candidates due to the hydrolytic lability of the pyrophosphate and triphosphate groups and their short half-lives in the bloodstream. Thus, there is a need in the art for functionally equivalent compounds, i.e., compounds that are isosterically and electronically identical to the natural pyrophosphates and triphosphates, but that are hydrolytically and enzymatically more stable, and preferably have reduced toxicity as well.
The present invention is addressed to the aforementioned need in the art, and provides an unprecedented class of nucleoside-based therapeutic agents containing a functional group that is isosterically and electronically identical to a natural pyrophosphate or triphosphate group, wherein the agents are hydrolytically and enzymatically more stable than the "natural" pyrophosphate and triphosphate compounds. The therapeutic agents now provided are useful in a variety of contexts, e.g., as antiviral agents, anticancer agents, metabolic moderators, and the like. The novel compounds are also useful as starting materials or intermediates in the synthesis of other nucleoside-based therapeutic agents, as research tools for studying nucleoside triphosphates and pyrophosphates (the naturally occurring compounds hydrolyze readily, resulting in inconvenience in the laboratory), and in the sequential preparation of oligonucleotides and polynucleotides of interest.